Induction of the interleukin-2/15 receptor β-chain by the EWS–WT1 translocation product

Abstract

EWS ± WT1 is a chimeric transcription factor resulting from fusion of the N-terminal domain of the Ewing sarcoma gene EWS to the three C-terminal zinc ®ngers of the Wilms tumor suppressor WT1. This translocation underlies desmoplastic small round cell tumor (DSRCT), which is noted for the abundance of reactive stroma surrounding islets of tumor cells, suggestive of paracrine signals contributing to tumor cell proliferation. Hybridization to high-density oligonucleotide microarrays can be used to identify targets of EWS ± WT1. Expression of EWS ± WT1 from a tetracycline-regulated promoter leads to the induction of growth-associated genes, of which the most remarkable is the beta-chain of the interleukin-2/15 receptor (IL-2/15Rb). Potent transcriptional activation by the chimeric protein maps to two bindings sites within the IL-2/15Rb promoter. Analysis of primary DSRCT tumor specimens demonstrates high levels of IL-2/15Rb within the tumor cells, along with expression of IL-2 and IL-15 by the abundant hyperplastic endothelial cells within the reactive stroma. Activation of this cytokine signaling pathway is consistent with the nuclear localization of its downstream eectors, phosphorylated STAT3 and STAT5. These observations suggest that the transcriptional induction of a cytokine receptor by a tumor-associated translocation product enables a proliferative response of epithelial cancer cells to ligands secreted by the surrounding stroma.

PDGF-A, PDGF-Rβ, TGFβ3 and bone morphogenic protein-4 in desmoplastic small round cell tumors with EWS-WT1 gene fusion product and their role in stromal desmoplasia: an immunohistochemical study

“…7,9 In addition, the EWS-WT1 chimeric protein has recently been shown to be a potent transcriptional activator of expression of the beta chain of the IL-2/15 receptor in tumor cells and expression of IL2 and IL-15 has been detected in the desmoplastic stroma in desmoplastic small round cell tumors. 13 The prominent stromal reaction might also provide a paracrine signal to neoplastic cell proliferation in these tumors. 13 Bone morphogenic proteins (BMP) are members of the TGF-b superfamily and have a complex role in regulating cell growth and differentiation including bone formation.…”

“…13 The prominent stromal reaction might also provide a paracrine signal to neoplastic cell proliferation in these tumors. 13 Bone morphogenic proteins (BMP) are members of the TGF-b superfamily and have a complex role in regulating cell growth and differentiation including bone formation. 14 Overexpression of BMP4 has been found in patients with fibrodysplasia ossificans progressiva and various bone and soft-tissue sarcomas.…”

EWS–WT1 Oncoprotein Activates Neuronal Reprogramming Factor ASCL1 and Promotes Neural Differentiation

“…Interestingly, the two isoforms differ in their oncogenic activities as only the EÀKTS, but not EþKTS, has the potential to transform NIH3T3 cells in vitro (17). Therefore, the majority of studies have focused on identifying the target genes of EÀKTS (18)(19)(20)(21)(22), whereas only two genes have been identified as direct targets of EþKTS (22,23). These studies also revealed different DNA recognition sequences of each isoform: EÀKTS binds to either a GC-rich, 5 0 -GXG(T/G)GGGXG-3 0 (X is any base; refs.…”

Formation of an active form of the interleukin‐2/15 receptor β‐chain by insertion of the intracisternal A particle in a radiation‐induced mouse thymic lymphoma and its role in tumorigenesis

“…The b-subunit, which is shared by IL-3R, granulocytemacrophage colony-stimulating factor receptor and IL-5R, is constitutively activated by extracellular truncation [24,25]. Similarly, there are genomic alterations that increase IL-2R expression in many tumor cells [26,27]. There are no reports, however, of structural alterations leading to cytokine-independent activation of IL-2R.…”